This study is designed to identify one or more conserved group A Streptococcus (GAS) proteins suitable for use as a safe and efficacious human vaccine worldwide. The key goal of the proposed research is to use genome-wide methods of contemporary vaccinology to identify one or more conserved GAS proteins that will significantly protect monkeys from pharyngitis caused by challenge with a strain expressing a heterologous M protein serotype. A conservative estimated timeline is that by the end of the 5-year research period, the antigen(s) will be ready for detailed toxicity testing prior to beginning phase I human trials. The international investigative team composed of academic and pharmaceutical industry collaborators proposes the following line of research involving a "reverse vaccinology" strategy: Aim 1: Use two mouse models of invasive GAS disease to confirm extensive preliminary data that novel candidate GAS antigens significantly protect immunized mice challenged with a GAS strain expressing a heterologous M protein serotype. Aim 2: Determine if the proteins satisfying the mouse screen criteria described in aim (1) above are conserved in natural populations of GAS, expressed on the cell surface of genetically diverse GAS strains, and expressed in vivo during diverse types of human infections (pharyngitis, invasive infections, etc). Aim 3: Use a recently-described monkey model that mimics human pharyngitis to determine if one or more of the candidate vaccine antigens we identify in aim (1) and (2) significantly protects against pharyngitis caused by a GAS strain expressing a heterologous M protein serotype.